Research Focus

Research in our laboratory is concerned with furthering our understanding of the molecular basis for several human diseases, including the neurodegenerative and neuromuscular diseases Friedreich’s ataxiaandmyotonic dystrophy,and the prevalent eye diseaseFuchs endothelial corneal dystrophy.These diseases share a common genetic basis, namely expansion of simple trinucleotide repeat sequences. Our efforts are also aimed at development of novel therapeutic approaches for these diseases.

Numerous studies have pointed to histone deacetylase (HDAC) inhibitors as potential therapeutics for various neurological and neurodegenerative diseases, and clinical trials with several HDAC inhibitors have been performed or are underway. However, the HDAC inhibitors that have been tested to date are either highly cytotoxic or have very low specificities for different HDAC enzymes. In the course of studies on Friedreich’s ataxia (FRDA), our laboratory identified a novel class of HDAC inhibitors (2-aminobenzamides) that reverse heterochromatin-mediated silencing of the frataxin (FXN) gene in this disease. Our studies show that these HDAC inhibitors cross the blood brain barrier in mice, exhibit no acute or chronic toxicity at potential therapeutic doses, and act as HDAC inhibitors in the mouse brain. Importantly, our compounds increase FXN mRNA levels in the brain and heart in a mouse model for FRDA. We have also derived a human neuronal cell model for FRDA based on differentiation of patient-derived induced pluripotent stem cells. These cells retain FXN gene silencing, exhibit repeat expansions as in the human disease, and respond to the HDAC inhibitors, yielding therapeutically beneficial levels of FXN gene expression. Compound libraries have been generated and screened for activity in the various cellular and mouse models and a clinical candidate has been identified and subjected to full pharmacological and toxicology testing. A phase I clinical trial in FRDA patients has been conducted, and based on these findings, compounds with improved pharmacological properties are being pursued in collaboration with BioMarin Pharmaceutical, Inc. We are also developing small molecule DNA ligands as transcription therapeutics for myotonic dystrophy and Fuchs endothelial corneal dystrophy. Both diseases are due to the transcription of toxic RNA species, and hence blocking expression of these pathogenic RNAs is an attractive approach for development of therapeutics.